Viable mutations of mouse midnolin suppress B cell malignancies.
Xue ZhongNagesh PeddadaJames J MorescoJianhui WangYiao JiangJonathan J RiosEva Marie Y MorescoJin Huk ChoiBruce A BeutlerPublished in: The Journal of experimental medicine (2024)
In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed in mice with targeted deletion of four of six MIDN protein isoforms. MIDN was expressed predominantly in lymphocytes where it augmented proteasome activity. We showed that purified MIDN directly stimulated 26S proteasome activity in vitro in a manner dependent on the ubiquitin-like domain and a C-terminal region. MIDN-deficient B cells displayed aberrant activation of the IRE-1/XBP-1 pathway of the unfolded protein response. Partial or complete MIDN deficiency strongly suppressed Eμ-Myc-driven B cell leukemia and the antiapoptotic effects of Eμ-BCL2 on B cells in vivo and induced death of Sp2/0 hybridoma cells in vitro, but only partially impaired normal lymphocyte development. Thus, MIDN is required for proteasome activity in support of normal lymphopoiesis and is essential for malignant B cell proliferation over a broad range of differentiation states.
Keyphrases
- cell proliferation
- induced apoptosis
- endoplasmic reticulum stress
- acute myeloid leukemia
- genome wide
- copy number
- peripheral blood
- small molecule
- bone marrow
- protein protein
- high throughput
- high glucose
- cell cycle arrest
- intellectual disability
- diabetic rats
- oxidative stress
- dna methylation
- drug induced
- gene expression
- signaling pathway
- adipose tissue
- endothelial cells
- drug delivery
- replacement therapy
- binding protein
- metabolic syndrome
- endoplasmic reticulum
- smoking cessation
- single cell